Summary of Work: Recent studies have shown that HIV-1 utilizes cell surface-bound CD4 molecules as well as chemokine receptors to enter and subsequently infect human T lymphocytes. Our laboratory has demonstrated that human T cells and antigen-specific T cell clones express significant levels of several chemokine receptors on their surface which mediate T-cell trafficking, degranulation, and intracellular calcium mobilization. Panels of human Th1 and Th2 clones differentially express several distinct chemokine receptors on the cell surface of these T helper cell subsets which may facilitate their selective T cell trafficking to inflammatory sites as well as mediate the selective entry of HIV-1 into these T cell subsets. However, despite these differences in chemokine receptor expression, our recent studies have demonstrated that human Th0, Th1, and Th2 clones are all capable of being infected with the various T-, M-, and dual-tropic strains of HIV-1. HIV-1-infected Th1 clones are rapidly infected with HIV-1; however, they also exhibit a rapid (1-5 day) Fas-mediated apoptosis in vitro compared to infected Th2 clones (4-21 days). The increased expression of Fas ligand on the surface of Th1 but not Th2 clones post HIV-1 infection may possibly explain the more rapid turnover of this CD4+ T cell subset. Further examination of the various apoptotic signaling differences between human Th1 and Th2 clones revealed that all human Th1 but not Th2 cells are susceptible to activation-induced cell death (AICD). In addition, the majority of human Th1 clones expressed low levels of the anti-apoptotic protein, bcl-2, making them more susceptible to various apoptotic stimuli as well as HIV-1 induced T cell death. In contrast, human Th2 clones, the majority of which express high levels of endogenous bcl-2, were less susceptible to apoptotic stimuli and HIV-1-mediated cytopathic effects. Thus, the protection of bcl-2-expressing T cells from HIV-induced cell death suggests that apoptosis not only contributes to cell killing by HIV infection but may also permit the selective destruction of Th1 cells in the periphery leading to a systemic Th2 response. As AIDS in the elderly population continues to increase in number and as a percentage of all new AIDS cases, it has been hypothesized that T cells obtained from elderly Over the next year, the Clinical Immunology Section will attempt to directly examine this question. patients express decreased levels of anti-apoptotic genes (e.g. bcl-2 and bcl-xl) and have an increases susceptibility to HIV-1.